Method for making very fine particles consisting of a principle inserted in a host molecule

ABSTRACT

The invention concerns a method for making very fine particles containing at least an active principle inserted in a host molecule and a device for implementing said method. The method is characterized in that it consists in forming a solution of the active principle in a first liquid solvent and of a product formed by the host molecules in a second liquid solvent, then in contacting the resulting solutions with a supercritical pressure fluid, so as to precipitate the host molecules which are dissolved therein.

[0001] The present invention relates to a method for making very fineparticles constituted by at least one active principle inserted in a“host” molecule, particularly of cyclodextrin type, as well as to adevice for carrying out this method. The present invention also concernsthe particles thus produced.

[0002] It is known that the pharmaceutical industry, but also thecosmetics industry and agrochemicals, are seeking novel formulations inorder to improve the efficiency of certain molecules of therapeutic,dermatological or plant protective interest. These industries are alsosearching for means making it possible to increase the solubility in thebiological media of insoluble, or very sparingly soluble, activeprinciples, in order to increase their bio-availability, to reduce thedoses administered and therefore to reduce the secondary effects. Theyare also seeking to avoid the loss of biological activity due to theproblems of instability in the aqueous media or during storage in thepresence of oxygen, of humidity of the air or of light. With a view tosolving these problems, it has been proposed to use differentexcipients, but without arriving at satisfactory solutions.

[0003] Various methods have been proposed for making fine particlesconstituted by an active principle which is inserted in a matrix, inorder to protect it against various physical or chemical degradations,or to facilitate its solubilization in aqueous solutions.

[0004] For some years, novel host molecules have been called upon, whichare adapted to form a molecular complex in which they enclose a moleculeof an active principle. Host molecules of cyclodextrin type are forexample known, whose development in the pharmaceutical industry ispromising at the present time. These molecules, of natural origin,issuing from the enzymatic degradation of starch, are producedindustrially and present the advantage of being biodegradable.Cyclodextrins are natural host molecules whose cyclic form allows themto “capture” a large variety of solid, liquid or gaseous substancesleading to the formation of “supermolecules”.

[0005] Advantage is generally taken of such a “capture” of the activeprinciples in order to modify the physico-chemical properties of themolecules captured and in particular their solubility, their stabilityand their reactivity. Moreover, numerous chemical groups (methyl-,hydroxypropyl-, carboxymethyl-, acetyl-) may be grafted on the naturalcyclodextrins by reaction with the hydroxyl groups, modifying theinteractions with the trapped substances. The random position and typeof substitution render these so-called “modified” cyclodextrinsamorphous, this contributing to considerably increasing their solubilityin water and in organic solvents. Methyl-β-cyclodextrin may thus becited, which is very soluble in water (3000 g/l), while not beinghygroscopic; it does not change the surface tension of the water whereit is dissolved and it is also soluble in methanol and ethanol.Moreover, it is admitted that this molecule may be used in oral,parenteral, nasal, transdermal, vaginal or rectal administration.

[0006] The present invention concerns a novel method making it possibleto effect the insertion at the molecular level of an active principle,particularly of pharmaceutical, cosmetological, dietetic or plantprotective interest, in a host molecule particularly of cyclodextrin ormodified cyclodextrin type and to make fine particles of this molecularcomplex, using a method employing a supercritical pressure fluid.

[0007] It will firstly be recalled that bodies are generally known inthree states, namely solid, liquid or gaseous, and that one passes fromone to the other by varying the temperature and/or the pressure. Now,there exists a point beyond which one can pass from the liquid state tothe state of gas or vapour without passing through a boiling or,inversely, through a condensation, but in continuous manner. This pointis called the critical point.

[0008] It is also known that a fluid in supercritical state is a fluidwhich is in a state characterized either by a pressure and a temperaturerespectively greater than the critical pressure and temperature in thecase of a pure body, or by a representative point (pressure,temperature) located beyond the envelope of the critical pointsrepresented on a diagram (pressure, temperature) in the case of amixture. Such a fluid presents, for numerous substances, a high solventpower with no comparison to that observed in this same fluid in thestate of compressed gas.

[0009] The same applies to so-called “subcritical” liquids, i.e. liquidswhich are in a state characterized either by a pressure higher than thecritical pressure and by a temperature lower than the criticaltemperature in the case of a pure body, or by a pressure higher than thecritical pressures and a temperature lower than the criticaltemperatures of the components in the case of a mixture (cf. MichelPERRUT—Les techniques de l'Ingénieur “Extraction par fluidesupercritique (Engineering Techniques “Extraction by supercriticalfluid), J 2 770-1 to 12, 1999”). In the following description,“supercritical pressure fluid” will designate a fluid taken to apressure higher than its critical pressure, whether it is insupercritical or subcritical state as defined hereinabove.

[0010] The considerable and modulatable variations of the solvent powerof supercritical pressure fluids are, moreover, used in numerous methodsof extraction (solid/fluid), of fractioning (liquid/fluid), ofanalytical or preparative chromatography, of treatment of materials(ceramics, polymers), of generation of particles, or as medium forcarrying out chemical or biochemical reactions. It should be noted thatthe physico-chemical properties of carbon dioxide as well as itscritical parameters (critical pressure: 7.4 MPa and criticaltemperature: 31° C.), make of it a preferred solvent in numerousapplications, all the more so as it does not present any toxicity and isavailable in very large quantities at very low cost. Other fluids mayalso be used under similar conditions, such as nitrogen protoxide, lighthydrocarbons having two to four carbon atoms, and certain halogenatedhydrocarbons.

[0011] It is known from numerous Patents and scientific publicationsthat supercritical pressure fluids, and particularly supercriticalcarbon dioxide, are widely used to make very fine powders of “micronic”or “submicronic” sizes capable of dissolving very rapidly or which canbe used by ingestion via the respiratory tracts. Fluids at supercriticalpressure are also studied with a view to obtaining very fine complexparticles formed by mixtures of different morphologies of the activeprinciple and of an excipient.

[0012] The majority of the systems described in the Patents andpublications are applied to an encapsulation of matricial type, whichconsists in integrating an active substance in a support particularly ofalginate, cellulosic derivatives, waxes, triglycerides, polysaccharides,or acrylic polymers type. Microspheres will be distinguished, which areconstituted by an active principle dispersed within an excipient of themicrocapsules, which are composed of a core of active substancesurrounded by a continuous envelope.

[0013] The so-called “RESS” technique (Debenedetti P., Journal ofControlled Release, 24, 1993, p. 27-44—Debenedetti P., Journal ofSupercritical Fluids, 7, 1994, p. 9-29) is based on forming a solutionof the active principle and of the excipient in the supercriticalpressure fluid. The atomization of this supercritical solution allowsthe formation of microspheres. However, this technique is limited by theweak solubility of the majority of the polymers and active substances inthe supercritical fluids.

[0014] The so-called anti-solvent methods, known under the designations“SAS, SEDS, PCA or ASES” allow the formation of compositemicro-particles. They describe the contacting of organic solutions ofactive principles and of excipient with a supercritical fluid. DifferentPatents describe various means for contacting the different fluids:Introduction of the supercritical fluid in the organic solution (PatentU.S. Pat. No. 5,360,478), separate spraying of the organic solution andof the supercritical fluid (Patents DE-A-3 744 329, U.S. Pat. No.5,043,280), use of coaxial nozzles with two or three inlets (Patents WO95/01221, WO 96/00610).

[0015] As for the so-called “PGSS” method, it allows the encapulsationof active principles by spraying at low pressure of a mixture of activeprinciple/excipient saturated by a supercritical fluid (PatentsEP-A-0744992, WO 95/21688).

[0016] The supercritical fluids thus make it possible to produce anencapsulation of membrane type by inclusion of active principles inliposomes (Patent U.S. Pat. No. 5,700,482).

[0017] The present invention has for an object to propose a method forthe preparation of fine particles constituted by at least one activeprinciple, insoluble or very sparingly soluble in aqueous solutions, andwhich is dispersed in molecular form in host molecules of cyclodextrintype, using a supercritical pressure fluid. This method makes itpossible to avoid, or to reduce to acceptable quantities from thetoxicological standpoint, the organic solvent residues present in theparticles obtained.

[0018] More particularly, this method makes it possible to prepare fineparticles of active principle, insoluble or very sparingly soluble inaqueous solutions, and which are inserted in a host molecule ofcyclodextrin type. In the case of the formulation of pharmaceuticalproducts, these particles present an increased bio-availability of theactive principle, and this whatever the mode of administration.

[0019] The present invention thus has for an object a method for makingvery fine particles containing at least one active principle, theseparticles being formed by an assembly of molecular complexes eachconstituted by a molecule of active principle inserted in a hostmolecule, characterized in that it comprises the steps consisting in:

[0020] forming a solution of the active principle in a first liquidsolvent and a product formed by the host molecules in a second liquidsolvent,

[0021] contacting the liquid solutions thus formed with a supercriticalpressure fluid, so as to reduce the solvent power of the liquid solventsand to cause the host molecules which are dissolved therein toprecipitate, by anti-solvent effect,

[0022] extracting the residual solvents by means of a supercriticalpressure fluid and evacuating the fluid/solvents mixture,

[0023] recovering the particles thus generated in the form of drypowder.

[0024] In a form of embodiment of the method according to the invention,in which the active principle is soluble in the supercritical pressurefluid, the latter may be used as solvent. Saturation of thesupercritical pressure fluid will preferably be ensured by causing it topercolate through a bed of particles of at least one active principle.

[0025] The present invention thus has for an object a method for makingvery fine particles containing at least one active principle, theseparticles being formed by an assembly of molecular complexes eachconstituted by a molecule of active principle inserted in a hostmolecule, characterized in that it comprises the steps consisting in:

[0026] forming a solution of the active principle in a first liquidsolvent constituted by a supercritical pressure fluid and a productformed by the host molecules in a second liquid solvent,

[0027] contacting the liquid solutions thus formed, so as to reduce thesolvent power of the liquid solvents and to cause the host moleculeswhich are dissolved therein to precipitate, by anti-solvent effect,

[0028] extracting the residual solvents by means of a supercriticalpressure fluid and evacuating the fluid/solvents mixture,

[0029] recovering the particles thus generated in the form of drypowder.

[0030] In a form of embodiment of the invention, the first and secondsolvents will be identical. The formation of solution of the activeprinciple and of the product formed by the host molecules and thecontacting of the solutions may also be effected during the same step.

[0031] According to the invention, the host molecule may be constitutedby at least one cyclodextrin of the α-cyclodextrine, or β-cyclodextrineor γ-cyclodextrin type. It may also be constituted by at least onecyclodextrin modified by grafting of a chemical group, particularly ofmethyl-α-cyclodextrin, hydroxypropyl-α-cyclodextrin,methyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin,carboxymethyl-β-cyclodextrine, or acetyl-β-cyclodextrin type.

[0032] The present invention also has for an object a device for makingvery fine particles comprising at least one active principle inserted ina host molecule, characterized in that it comprises an atomizationchamber of which the upper part is provided with spraying means whichare supplied on the first hand with a liquid solution of at least oneactive principle, on the second hand with a liquid solution of a matrixof cyclodextrin, and on the third hand with a supercritical pressurefluid, the lower part of the atomization chamber is provided with meansfor recovering the micro-particles formed and with an outlet for thesupercritical pressure fluid which is connected to separation means,particularly of cyclonic type, and drawing-off elements allowing arecycling of the fluid towards a storage tank.

[0033] The spraying means may be constituted by a nozzle allowing thesimultaneous introduction of the solution of at a least one activeprinciple, and of the liquid solution of cyclodextrine matrix. In a formof embodiment of the invention, the nozzle will, in addition, allow thesimultaneous introduction of the supercritical pressure fluid. Thisspraying nozzle may comprise an inner collector volume in which convergeupstream channels in communication with the fluids which it is desiredto spray in the atomization chamber and an outlet channel incommunication with the atomization chamber.

[0034] The present invention also has for an object a productconstituted by very fine particles containing at least one activeprinciple, characterized in that these particles are formed by anassembly of molecular complexes each constituted by a molecule of activeprinciple inserted in a host molecule.

[0035] In the usual configuration, the method makes it possible tointroduce, separately, a solution of an active principle or of a mixtureof active principles, a solution of host molecules of cyclodextrin type,and a supercritical pressure fluid, the formation of the complex of theactive principle or principles and of the matrix taking place in arecipient under pressure, during the precipitation phase.

[0036] According to a variant, the active principle, or the mixture ofactive principles, and the product formed by the host molecules,particularly of cyclodextrin type, are dissolved in the same liquidsolvent, and these solutions may be introduced in mixture in therecipient under pressure swept by the supercritical pressure fluid; inthis case, the active principle(s)/host molecule complex may be formedbefore the contacting with the supercritical pressure fluid or duringthe precipitation phase.

[0037] The inserted particles will preferably have a diameter includedbetween 0.01 μm and 30 μm and will be constituted in particular by anactive principle of alimentary, pharmaceutical, cosmetic, agrochemicalor veterinary interest. Furthermore, and although another gas may beused, the supercritical pressure fluid will favourably be constituted bycarbon dioxide, possibly having a volatile organic solvent, of lighthydrocarbon, alcohol, ester, ketone or halocarbon type, added thereto.Whatever their diameter, these particles will be designated in thepresent text by fine particles.

[0038] It will be noted that the supercritical pressure fluid laden withorganic solvents may be recycled in accordance with the methodsconventionally used in supercritical extraction/fractioning, inparticular by using devices of the type such as those described inFrench Patent FR-A-2 584 618.

[0039] On the other hand, the contacting of the active principle/hostmolecule complex and of a supercritical pressure fluid makes it possibleto effect simultaneously the precipitation and the drying of theparticles under mild conditions, which makes of it a choice techniquefor encapulsation of fragile products, such as for example proteins.

[0040] From a practical standpoint, the contacting of the supercriticalfluid with the solution(s) of active principle(s) and of host moleculeis either effected by introduction of the supercritical pressure fluidin an autoclave already containing the solution, or by spraying of thesolution(s) through one or more nozzles in an autoclave swept bysupercritical pressure fluid. The nozzles used may present differentconfigurations: separate inlets of the solution or the solutions and thesupercritical fluid, or single inlet allowing the contacting of the twofluids just in front of the orifice of the nozzle so that the speed ofthe supercritical fluid makes it possible to spray the liquid solutionin very fine droplets.

[0041] Various forms of embodiment of the present invention will bedescribed hereinafter by way of non-limiting example with reference tothe accompanying drawing, in which:

[0042]FIG. 1 schematically shows an installation for producing fineparticles of at least one active principle encapsulated in a hostmolecule of cyclodextrin type, according to the invention.

[0043]FIG. 2 is a view in axial section of an example of implementationof a spraying nozzle used in the device according to the invention.

[0044] This device is essentially constituted by an atomization chamber1 of which the upper part is provided with a spraying nozzle 3 which issupplied with liquefied gas via a pipe 5 connected to a storage tank 7.A pump 9 and an exchanger 11 make it possible to take the liquefied gasto supercritical state. The solution of the active principle, or of themixture of active principles, in an organic or aqueous solvent iscontained in a recipient 13 and is taken to the spraying nozzle 3 via aconduit 17 under the action of a pump 15. Similarly, the solution ofhost molecule, particularly of cyclodextrin or modified cyclodextrintype, in an organic or aqueous solvent is contained in a recipient 19and is taken to the spraying nozzle 3 via a conduit 23 under the actionof a pump 21. The lower part of the atomization chamber 1 is providedwith an outlet of the supercritical pressure fluid 25 which is connectedto cyclonic separators 31 via a regulation valve 27 and a filter 29. Theoutlet of the separators 31 is connected to drawing-off elements 33. Thelast separator 31 is connected to the storage tank 7 by a conduit 37traversing a condenser 35.

[0045] According to the invention, there are simultaneously injectedinto the atomization chamber 1 the solutions of active principle, or ofthe mixture of active principles contained in the recipient 13, thesolution of the host molecule, contained in the recipient 19, and thegas contained in the tank 7 which is taken to the supercritical state bythe pump 9 and the exchanger 11.

[0046] In the course of this operation, the flux of supercriticalpressure fluid entrains the solvent in which is dissolved the activeprinciple and the host molecule in the form of complex or not, which hasthe effect of increasing their concentration beyond saturation, thusprovoking the precipitation of the products in complexed form. The fineparticles obtained are separated from the supercritical fluid,containing the organic or aqueous solvents, by passage through afiltering element 14, disposed at the bottom of the atomization chamber1, and which is constituted for example by a disc of sintered metal orby a woven or non-woven textile.

[0047] At the outlet of the atomization chamber 1, the solvent-ladenfluid is partially expanded to the pressure of recycling through theregulation valve 27 and reheated in cyclonic separators 31 afterfiltration through the filter 29.

[0048] The collected solvent is drawn off in liquid phase at atmosphericpressure by the drawing-off elements 33. The fluid, from which the majorpart of the solvent has been removed, is recycled by liquefaction in thecondenser 35 towards the tank of liquid fluid 7. The addition of fluidin the liquid or gaseous state is effected via an inlet 8.

[0049] According to an interesting variant of the invention,particularly favourable to obtaining particles of very small diameter,the solutions of active principle and of the host molecule as well asthe supercritical pressure fluid are introduced through a single nozzle3′ particularly of the type such as that shown in FIG. 2 and which willbe described hereinafter.

[0050] When the quantity of fine particles fixed on the filteringelement 14 is sufficient, the pumping of the solutions of activeprinciple and of host molecule is interrupted. The small quantities ofsolvent present in the fine particles may then be eliminated by causinga stream of carbon dioxide in the supercritical state to percolatethrough the bed of these particles deposited on the filtering element14. After total elimination of this solvent, the atomization chamber 1is depressurized and the fine particles recovered on the filteringelement 14.

[0051] In a variant embodiment of the invention, the active principle,or the mixture of active principles, and the product constituted by hostmolecules are dissolved in the same solvent. In this form of embodiment,one sole pump 15 or 21 is in that case necessary for injecting thesolution in the atomization chamber 1 by means of the spraying nozzle 3.

[0052] The spraying nozzle 3′ shown in FIG. 2 is constituted by acylindrical metal pellet of which the upstream principal face ishollowed out with three channels 2, 4, 6, which converge in a collectorchamber 10 and which ensure supply thereof with solution of activeprinciple, with solution of host molecule as well as with supercriticalpressure fluid. The latter is itself in communication with thedownstream outlet of the nozzle 3′ via an axial pipe 12.

[0053] In order to illustrate the present invention, the followingexamples of embodiment will be cited, employed on an installation ofsemi-industrial size having a service pressure of 30 MPa and atemperature range going from 0° C. to 150° C., constructed in accordancewith the diagram shown in FIG. 1.

[0054] Carbon dioxide was used as supercritical pressure fluid. Thediaphragm pump 9 allowed a flowrate of the order of 6 kg/hr. to 20kg/hr. of carbon dioxide under a pressure of 30 MPa, the solution supplypumps 15 and 21 allowed a flowrate of 0.05 kg/hr to 0.75 kg/hr. ofliquid at 30 Mpa, the fluid tank 7 having a total volume of 2 litres,the atomization chamber 1 being constituted by a tubular recipient ofvertical axis, of diameter 0.1 m and with a total volume of 4 litres,provided on its section, at the bottom of the recipient, with afiltering element 14 constituted by a membrane of non-woven glassmicrofibers with a porosity of 0.7 μm supported by a disc of sinteredmetal with a porosity of 50 μm.

EXAMPLE 1

[0055] By means of the installation thus described, there was generateda powder of very fine particles of complex formed by a steroid,prednisolone, and by methyl-β-cyclodextrin, by spraying a solutioncontaining 0.32% by mass of prednisolone and 2.5% by mass ofmethyl-β-cyclodextrin, viz. a mol ratio of 1:2, in absolute ethanol witha flowrate of 0.5 kg/hr. in a stream of 15 kg/hr. of carbon dioxide at15 MPa and 40° C. The active principle and the matrix being formed insolution in the ethanol concomitantly, only one pump 15 for introductionin the atomization chamber 1 was used. This liquid solution and thesupercritical pressure fluid were introduced in the chamber 1 via asingle nozzle 3′, the two fluids mixing in the cavity 10 with a volumeclose to 0.5 ml made in the body of the nozzle 3′, placed incommunication with the atomization chamber 1 via the conduit 12 providedwith an orifice with a diameter of 0.06 mm.

[0056] After an hour of spraying, the introduction of solution of activeprinciple was stopped and a stream of carbon dioxide at 15 MPa and at40° C. was made to percolate in the bed of particles fixed on thefiltering element. The carbon dioxide was then sent towards theseparators where the organic solvent was recovered. Afterdepressurization of the atomization chamber 1, the micro-particles fixedon the filtering element 14 were recovered.

[0057] The characteristics of the recovered fine particles are thefollowing:

[0058] granulometric distribution: 90% of the particles have a diameterincluded between 0.8 μm and 3.5 μm and a mean diameter of 1.4 μm.

[0059] composition by mass: 11% of prednisolone and 85% ofmethyl-β-cyclodextrin.

[0060] The content of organic solvent in the fine particles, determinedby gaseous phase chromatography of the aqueous phase obtained byprolonged stirring of the powder under ultrasounds, is less than 100ppm, which allows the use of these particles without supplementarytreatment.

EXAMPLE 2

[0061] By means of the installation described hereinbefore, there wasgenerated a powder of very fine particles of complex formed by ananti-inflammatory, ibuprofen, and by methyl-β-cyclodextrin, by sprayinga solution containing 0.22% by mass of ibuprofen and 3.0% by mass ofmethyl-β-cyclodextrin, viz. a mol ratio of 1:2, in acetone with aflowrate of 0.5 kg/hr. in a stream of 15 kg/hr. of carbon dioxide at 15MPa and 40° C. After an hour of spraying, the introduction of solutionof active principle was stopped and a stream of carbon dioxide at 15 MPaand at 40° C. is made to percolate in the bed of particles fixed on thefiltering element. The carbon dioxide was then sent towards theseparators where the organic solvent was recovered. Afterdepressurization of the atomization chamber, the fine particles fixed onthe filtering element 14 were recovered.

[0062] The characteristics of the recovered fine particles are thefollowing:

[0063] granulometric distribution: 90% of the fine particles have adiameter included between 0.7 μm and 2.9 μm and a mean diameter of 1.1μm.

[0064] composition by mass: 8% of ibuprofen and 92% ofmethyl-β-cyclodextrin.

[0065] The content of organic solvent in the fine particles, deterninedby gaseous phase chromatography of the aqueous phase obtained byprolonged stirring of the powder under ultrasounds, is less than 100ppm, which allows the use of these fine particles without supplementarytreatment.

[0066] It has been observed that, although the host molecules whichprove most interesting are cyclodextrins and modified cyclodextrins, itis possible according to the invention to call upon other types of hostmolecules such as in particular ring ethers.

1. Method for making very fine particles containing at least one activeprinciple, these particles being formed by an assembly of molecularcomplexes each constituted by a molecule of active principle inserted ina host molecule, characterized in that it comprises the steps consistingin: forming a solution of the active principle in a first liquid solventand a product formed by the host molecules in a second liquid solvent,contacting the liquid solutions thus formed with a supercriticalpressure fluid, so as to reduce the solvent power of the liquid solventsand to cause the host molecules which are dissolved therein toprecipitate, by anti-solvent effect, extracting the residual solvents bymeans of a supercritical pressure fluid and evacuating thefluid/solvents mixture, recovering the particles thus generated in theform of dry powder.
 2. Method for making very fine particles containingat least one active principle, these particles being formed by anassembly of molecular complexes each constituted by a molecule of activeprinciple inserted in a host molecule, characterized in that itcomprises the steps consisting in: forming a solution of the activeprinciple in a first liquid solvent constituted by a supercriticalpressure fluid and a product formed by the host molecules in a secondliquid solvent, contacting the liquid solutions thus formed, so as toreduce the solvent power of the liquid solvents and to cause the hostmolecules which are dissolved therein to precipitate, by anti-solventeffect, extracting the residual solvents by means of a supercriticalpressure fluid and evacuating the fluid/solvents mixture, recovering theparticles thus generated in the form of dry powder.
 3. Method accordingto claim 2, characterized in that the supercritical pressure fluid issaturated with active principle before it is contacted with the liquidsolution.
 4. Method according to claim 3, characterized in thatsaturation of the supercritical pressure fluid with active principle isobtained by causing it to percolate through a bed of particles of atleast one active principle.
 5. Method according to claim 1,characterized in that the first and second solvents are identical. 6.Method according to claim 5, characterized in that the formation ofsolution of the active principle and of the product formed by the hostmolecules and the contacting of the solutions thus formed are effectedduring the same step.
 7. Method according to one of the precedingclaims, characterized in that the supercritical pressure fluid is carbondioxide.
 8. Method according to one of the preceding claims,characterized in that the host molecule is constituted by cyclodextrinof the α-cyclodextrine, or β-cyclodextrine or γ-cyclodextrin type. 9.Method according to one of claims 1 to 7, characterized in that the hostmolecule is constituted by at least one modified cyclodextrin ofmethyl-α-cyclodextrin, hydroxypropyl-α-cyclodextrin, ormethyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, orcarboxymethyl-β-cyclodextrine, or acetyl-β-cyclodextrin type.
 10. Methodaccording to one of claims 1 or 2, characterized in that the hostmolecule is constituted by at least one cyclodextrin modified bygrafting of a chemical group.
 11. Method according to one of thepreceding claims, characterized in that the active principle is acompound of pharmaceutical, cosmetological, dietetic or plant-protectiveinterest.
 12. Device for making very fine particles comprising at leastone active principle inserted in a host molecule, characterized in thatit comprises an atomization chamber (1) of which the upper part isprovided with spraying means (3, 3′) which are supplied on the firsthand with a liquid solution of at least one active principle, on thesecond hand with a liquid solution of a host molecule of cyclodextrintype, and on the third hand with a supercritical pressure fluid, thelower part of the atomization chamber (1) is provided with means (14)for recovering the micro-particles formed and with an outlet (10) forthe supercritical pressure fluid which is connected to separation means(31), particularly of cyclonic type, and drawing-off elements (33)allowing a recycling of the fluid towards a storage tank (7).
 13. Deviceaccording to claim 12, characterized in that the spraying means areconstituted by a nozzle (3′) allowing the simultaneous introduction ofthe solution of at a least one active principle, and of the liquidsolution of cyclodextrine matrix.
 14. Device according to claim 13,characterized in that the nozzle (3′) further allows the simultaneousintroduction of the supercritical pressure fluid.
 15. Device accordingto one claims 13 or 14, characterized in that the spraying nozzle (3′)comprises an inner collector volume (10) in which converge upstreamchannels (2, 4, 6) in communication with the fluids which it is desiredto spray in the atomization chamber (1) and an outlet channel (12) incommunication with this atomization chamber (1).
 16. Product constitutedby very fine particles containing at least one active principle,characterized in that these particles are formed by an assembly ofmolecular complexes each constituted by a molecule of active principleinserted in a host molecule.